Constitutive Occurrence of E:N-cadherin Heterodimers in Adherens Junctions of Hepatocytes and Derived Tumors

Tiemo Sven Gerber; Dirk Andreas Ridder; Mario Schindeldecker; Arndt Weinmann; Diane Duret; Kai Breuhahn; Peter R Galle; Peter Schirmacher; Wilfried Roth; Hauke Lang; Beate Katharina Straub

doi:10.3390/cells11162507

Constitutive Occurrence of E:N-cadherin Heterodimers in Adherens Junctions of Hepatocytes and Derived Tumors

Cells. 2022 Aug 12;11(16):2507. doi: 10.3390/cells11162507.

Authors

Affiliations

¹ Institute of Pathology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
² Tissue Biobank, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
³ 1st Department of Internal Medicine, Gastroenterology and Hepatology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
⁴ Institute of Pathology, University Clinic Heidelberg, 69120 Heidelberg, Germany.
⁵ Department of General, Visceral and Transplant Surgery, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.

Abstract

Cell-cell junctions are pivotal for embryogenesis and tissue homeostasis but also play a major role in tumorigenesis, tumor invasion, and metastasis. E-cadherin (CDH1) and N-cadherin (CDH2) are two adherens junction's transmembrane glycoproteins with tissue-specific expression patterns in epithelial and neural/mesenchymal cells. Aberrant expression has been implicated in the process of epithelial-mesenchymal transition (EMT) in malignant tumors. We could hitherto demonstrate cis-E:N-cadherin heterodimer in endoderm-derived cells. Using immunoprecipitation in cultured cells of the line PLC as well as in human hepatocellular carcinoma (HCC)-lysates, we isolated E-N-cadherin heterodimers in a complex with the plaque proteins α- and β-catenin, plakoglobin, and vinculin. In confocal laser scanning microscopy, E-cadherin co-localized with N-cadherin at the basolateral membrane of normal hepatocytes, hepatocellular adenoma (HCA), and in most cases of HCC. In addition, we analyzed E- and N-cadherin expression via immunohistochemistry in a large cohort of 868 HCCs from 570 patients, 25 HCA, and respective non-neoplastic liver tissue, and correlated our results with multiple prognostic markers. While E- or N-cadherin were similarly expressed in tumor sites with vascular invasion or HCC metastases, HCC with vascular encapsulated tumor clusters (VETC) displayed slightly reduced E-cadherin, and slightly increased N-cadherin expression. Analyzing The Cancer Genome Atlas patient cohort, we found that reduced mRNA levels of CDH1, but not CDH2 were significantly associated with unfavorable prognosis; however, in multivariate analysis, CDH1 did not correlate with prognosis. In summary, E- and N-cadherin are specific markers for hepatocytes and derived HCA and HCC. E:N-cadherin heterodimers are constitutively expressed in the hepatocytic lineage and only slightly altered in malignant progression, thereby not complying with the concept of EMT.

Keywords: adherens junctions; cadherin; cell-cell contacts; epithelial–mesenchymal transition; liver tumors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adherens Junctions / metabolism
Cadherins / metabolism
Carcinoma, Hepatocellular* / pathology
Hepatocytes / metabolism
Humans
Liver Neoplasms* / pathology
Protein Multimerization

Substances

Cadherins

Grants and funding

T.S.G. and D.A.R. are supported by the Clinician Scientist Fellowship “Else Kröner Research College: 2018_Kolleg.05”. K.B. was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation): SPP1782 (414059188). Additionally, D.A.R. received funding from the Level I Program of the University Medical Center Mainz.